Inflammation plays a fundamental role in host defenses and the progression of immune-mediated diseases. The inflammatory response is initiated in response to an injury (e.g. trauma, ischemia, and foreign particles) and/or an infection (e.g. bacterial or viral infection) by, including chemical mediators (e.g. cytokines and prostaglandins) and inflammatory cells (e.g. leukocytes). It is characterized by increased blood flow to the tissue, causing pyrexia, erythema, induration and pain.
A delicate well-balanced interplay between the humoral and cellular immune elements in the inflammatory response enables the elimination of harmful agents and the initiation of the repair of damaged tissue. When this delicately balanced interplay is disrupted, the inflammatory response may result in considerable damage to normal tissue and may be more harmful than the original insult that initiated the reaction. In these cases of uncontrolled inflammatory responses, clinical intervention is needed to prevent tissue damage and organ dysfunction. Diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease, asthma, allergies, septic shock syndrome, atherosclerosis, inflammatory bowel disease among other clinical conditions are characterized by chronic inflammation.
Several proinflammatory cytokines, especially TNF-α (tumor necrosis factor-α) and interleukins (IL-1β, IL-6, IL-8) play an important role in the inflammatory process. Both IL-1 and TNF-α are derived from mononuclear cells and macrophages and in turn induce the expression of a variety of genes that contribute to the inflammatory process.
Rheumatoid arthritis (RA) is an autoimmune disorder. RA is a chronic, systemic, articular inflammatory disease of unknown etiology. In RA, the normally thin synovial lining of joints is replaced by an inflammatory, highly vascularized, invasive fibrocollagenase tissue (pannus), which is destructive to both cartilage and bone. Areas that may be affected include the joints of the hands, wrists, neck, jaw, elbows, feet and ankles. Cartilage destruction in RA is linked to aberrant cytokines and growth factor expression in the affected joints.
Osteoarthritis (OA, also known as degenerative arthritis, degenerative joint disease), is the most common type of arthritis involving degradation of joints, including articular cartilage and the subchondral bone next to it. In OA, a variety of potential forces, hereditary, developmental, metabolic, and mechanical, may initiate processes leading to loss of cartilage, a strong protein matrix that lubricates and cushions the joints. When bone surfaces become less well protected by cartilage, subchondral bone may be exposed and damaged, with regrowth leading to a proliferation of ivory-like, dense, reactive bone in central areas of cartilage loss, a process called eburnation. Due to decreased movement because of the pain, regional muscles may atrophy, and ligaments may become more lax. OA is the most common form of arthritis, and the leading cause of chronic disability.
Inflammatory bowel disease (IBD) is a group of disorders that cause inflammation of the intestines. The inflammation lasts for a long time and usually relapses. The two major types of IBD are Crohn's disease and ulcerative colitis. Crohn's disease occur when the lining and wall of the intestines becomes inflamed resulting in the development of ulcers. Although Crohn's disease can occur in any part of the digestive system, it often occurs in the lower part of the small intestine where it joins the colon. Ulcerative colitis is a chronic auto-immune/inflammatory disease of unknown etiology afflicting the large intestine and affecting millions of people worldwide. It is well-established that a dysfunctional immune-response involving components of normal gastrointestinal gram-negative bacteria and increased expression of pro-inflammatory cytokines, chemokines, endothelial cell adhesion molecules (ECAMs) and enhanced leukocyte infiltration into colonic interstitium, play a key role in the pathogenesis of colitis. The course of the disease may be continuous or relapsing, mild or severe. The earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkuhn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration. Signs and symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus, and mucus with scanty fecal particles. A total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.
Psoriasis is a chronic, non-contagious autoimmune disease which affects the skin and joints. It commonly causes red scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Ten to fifteen percent of people with psoriasis have psoriatic arthritis. There are many treatments available, but because of its chronic recurrent nature, psoriasis is difficult to treat.
Tumor Necrosis Factor-α (TNF-α), a pleiotropic cytokine, is produced mainly by macrophages, but other types of cells also produce it. TNF-α demonstrates beneficial as well as pathological activities. It has both growth stimulating effects and growth inhibitory properties, besides being self-regulatory. The beneficial functions of TNF-α include maintaining homeostasis by regulating the body's circadian rhythm, mounting an immune response to bacterial, viral, fungal and parasitic infections, replacing or remodeling injured tissue by stimulating fibroblast growth and, as the name suggests, killing certain tumors. TNF-α is derived from mononuclear cells and macrophages and in turn induces the expression of a variety of genes that contribute to various disorders such as inflammatory disorders.
Although TNF-α plays a critical role in innate and acquired immune responses, inappropriate production of TNF-α produce pathological changes resulting in chronic inflammation and tissue damage. TNF-α has been shown to play a crucial role in the pathogenesis of many chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, ulcerative colitis, psoriasis, adult respiratory distress syndrome, diabetes, skin delayed type hypersensitivity disorders and Alzheimer's disease.
IL-1 (Interleukin 1) is an important part of the innate immune system, which regulates functions of the adaptive immune system. The balance between IL-1 and IL-1 receptor antagonist (IL-1ra) in local tissues influences the possible development of an inflammatory disease and resultant structural damage. In the presence of an excess amount of IL-1, inflammatory and autoimmune disorders may be developed in joints, lungs, gastrointestinal tract, central nervous system (CNS) or blood vessels.
Cellular adhesion molecules intercellular adhesion molecule1 (ICAM-1), vascular-cell adhesion molecule1 (VCAM-1), and E-Selectin are responsible for the recruitment of inflammatory cells, such as neutrophils, eosinophils, and T lymphocytes, from the circulation to the site of inflammation. The recruitment and retention of leukocyte is a critical event in the pathogenesis of all chronic inflammatory diseases such as RA.
The first line of treatment for inflammatory disorders involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, naproxen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Moreover, NSAIDs merely treat the symptoms of the inflammatory disorder and not the cause. When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant side effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
Although phosphodiesterase-4 (PDE4) inhibitors have been developed for the treatment of asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, and Crohn's disease, the non-selective inhibition of multiple PDE4s leads to complex physiological responses. The therapeutic potential of PDE4 inhibitors has been hampered by their dose-limiting side effects of nausea and emesis as in the case of Cilomilast (SB 207499, Ariflo™) (Current Opinion in Chemical Biology, 2001, 5, 432-438).
Similarly, although p38 mitogen-activated protein kinase (MAPK) inhibitors are potential anti-inflammatory agents, the side-effects associated with their use include gastric ulcerations, hepatotoxicity, and nephrotoxicity. For instance, development of 2-[2(S)-Amino-3-phenylpropylamino]-3-methyl-5-(2-naphthyl)-6-(4-pyridyl)pyrimidin-4(3H)-one (AMG 548, Amgen) was suspended due to random liver enzyme elevations that were not dose or exposure dependent. The impact on safety profiles after chronic treatment using p38 MAP kinase inhibitors, needs to be established (Current Medicinal Chemistry, 2005, 12, 2979-2994).
U.S. Pat. No. 4,900,727 discloses benzopyran-4-one derivatives as antiinflammatory agents. Anti-inflammatory benzopyran-4-one derivative from Dysoxylum binectariferum is described by R. G. Naik et al in Tetrahedron, 1988, 44 (7), 2081-2086.
Notwithstanding the availability of a number of therapies for the treatment of inflammatory disorders, there still exists a continuing need for improved and alternative medicaments for the treatment of inflammatory disorders.
U.S. Pat. No. 7,271,193, Published US application US20070015802, and published PCT application, WO2007148158, all of which are incorporated herewith in all entirety as references, describe pyrrolidine substituted flavones as CDK inhibitors with utility in the treatment of different types of cancers. The present inventors have found that the pyrrolidine substituted flavones designated herein as compounds of formula 1 find use in the treatment of inflammatory disorders. The scope of the present invention is to provide a new anti-inflammatory use of the above-mentioned pyrrolidine substituted flavones.